Pre- and post-operative psychological interventions to prevent pain and fatigue after breast cancer surgery (PREVENT): Protocol for a randomized controlled trial

Background Breast cancer is the most common cancer type among women worldwide with over a million new cases each year. More than 40% of these women will struggle with chronic pain and fatigue after surgery, regardless of surgical procedure. These consequences are detrimental and result in distress and disability, including work disability. Few attempts have been made to prevent chronic pain and fatigue after surgery by applying a psychological approach, despite psychological risk factors being crucial in the development of both chronic pain and fatigue. In this study, we aim to develop and test an easily implementable strategy of preventing chronic pain and fatigue after breast cancer surgery. The intervention strategy involves a pre-operative hypnosis session and a web-based post-operative Acceptance and Commitment Therapy (ACT). The hypnosis has previously been found effective in alleviating acute post-operative pain and fatigue in breast cancer patients, while ACT is well suited to cancer populations as it offers a model of healthy adaptation to difficult circumstances. Together they form an intervention strategy with both a preventive and a rehabilitative focus. Methods/Design This randomized controlled trial aims to estimate the effects of the pre- and post- operative interventions compared to attentional control and treatment as usual (TAU) and will also include a qualitative process evaluation. Participants will be randomized to receive either a pre-operative brief hypnosis session and a post-operative web-based psychological intervention (iACT) or a pre-operative one-session mindfulness through an audio file and post-operative TAU. Self-reported questionnaire data and biomarker data will be assessed pre-surgery, post-surgery and 3 and 12 months after surgery. In addition, we will assess registry data on sick leave and prescriptions until 2-year follow-up. In the qualitative process evaluation, data will be collected from participants from both study arms (through interviews and a diary) and two different analyses performed (socio-narrative and Grounded Theory) with the objective to describe the development of chronic post-surgical pain and fatigue and the potential influence of the interventions on these processes. The study is set-up to demonstrate a minimum difference in pain of 1 point on NRS (0–10) and 3 points on FACIT-F (0–52) between the groups at 3-months follow-up by including 200 breast cancer patients in total. Discussion This trial will be the first study to estimate the effect of a combined pre-operative hypnosis with a post-operative iACT to prevent pain and fatigue after breast cancer surgery. The results from our study might i) help the large group of women affected by chronic pain and fatigue after breast cancer surgery, ii) shed light on the mechanisms involved in chronic pain and fatigue development, and iii) serve as a model for other surgical procedures. Trial registration Clinicaltrials.gov, registration number NCT04518085. Registered on January 29th, 2020. https://clinicaltrials.gov/ct2/show/NCT04518085.


Background
Breast cancer is the most common cancer type among women, with >1 million new cases worldwide every year (1). Survival rates for breast cancer is increasing (2), but for many patients survivorship is also characterized by disabling psychological and physical late effects (3)(4)(5). Chronic post-surgical pain (CPSP) and persistent fatigue have the most profound prevalence. CPSP has prevalence rates ranging from 25-60% depending on definition, measurement and treatment (6). In a recent Norwegian study, more than 40% of women treated for breast cancer continued to have pain 2-6 years after surgery (7), while over a third of the women in a large Danish study reported persistent pain 5-7 years after surgery (8).
Persistent fatigue is the most common symptom associated with cancer and its treatments (9).
Still, studies on the occurrence of and predictors of fatigue after surgery are scarce. One of the few studies investigating persistent fatigue after surgery reported high levels of fatigue in the first two months after surgery, followed by mild-to-moderate levels of fatigue that persisted 12 months after surgery (10). In another post-operative study, a third of the women struggled with persistent fatigue up to 10 years into survivorship (11) The pathophysiology of CPSP is still unclear. Presumably, the nature of most CPSP is neuropathic since surgery (e.g. mastectomy) may involve major nerve damage, and is associated with the highest incidence of such pain (12,13). However, many patients with CPSP do not show any signs of neuropathic pain, or any sensory changes (3). It is thus assumed that the distinct pathophysiology reflects both peripheral and central sensitization as well as humoral factors contributing to pain. Further, the etiology of chronic pain is grounded in the bio-psycho-social model, where psychological and social factors contribute to the development of CPSP (14). The pathophysiology of post-surgical fatigue is also largely unclear (15). The underlying mechanisms likely vary from patient to patient, with a mixture of biological and psychological underpinnings (16). Interestingly, there are several shared risk factors between pain and fatigue after surgery, including depression and outcome expectancies (17), implying that the very same processes might influence both post-surgical pain and fatigue.
Despite strong evidence supporting the role of psychological factors in the development of CPSP and fatigue, hardly any studies have investigated psychological and behavioral interventions aimed at preventing these symptoms. CPSP and fatigue management, however, has been the aim of several psychological and behavioral interventions. Mindfulness-based cognitive therapy on persistent pain after breast cancer surgery was recently found effective in reducing pain intensity (25), and a study led by a member of our project group found beneficial effects of CBT plus hypnosis to control fatigue in patients undergoing radiotherapy for breast cancer (26). Several studies of similar psychological interventions exist, but with limited effects (27,28), and with no preventive focus (29)(30)(31).
Hypnosis is a non-pharmacotherapeutic technique that holds promise as a harmless and effective pre-operative intervention to alleviate acute post-surgical pain and fatigue (32,33).
Clinical research with at least 20 different surgical populations has indicated that hypnosis can reduce the need for medication, reduce post-surgical symptoms, and enhance recovery (33). Furthermore, meta-analyses (34), narrative reviews (35,36), and randomized clinical studies (37)(38)(39)(40) all support the potential clinical utility of hypnosis with surgical breast cancer patients. A rigorous trial from 2007 demonstrated particularly large effects of a specific 15minute pre-operative hypnosis on analgesic needs, pain intensity and fatigue after breast cancer surgery (41). However, the results from this trial have not been replicated, and results from hypnosis trials in general lack long-term follow-up.
Acceptance and Commitment Therapy (ACT) is an evidence-based treatment for persistent pain (42,43) and is also a good fit for treating persistent fatigue (44). ACT is well suited to cancer populations as it offers a model of healthy adaptation to difficult circumstances and has shown promise in the treatment of opioid misuse (45). There have been several calls to expand the scope of ACT interventions to the treatment of CPSP (46). In a recent initiative, ACT was applied as treatment for CPSP in The Toronto General Hospital, with preliminary promising results. Those receiving ACT demonstrated greater reductions in opioid use and pain interference, as well as reductions in depressed mood, compared to those who received treatment as usual (follow-up form medical doctor) (47,48). In addition to being an evidencebased treatment for pain and fatigue, ACT is also among the very few psychological treatments with documented effects on return-to-work (49). Moreover, in a Norwegian study from members of the project group, a miniscule ACT follow-up intervention consisting of 1-6 phone calls, eased patients transition into the workplace (50) Despite the fact that both CPSP and persistent fatigue are common consequences of breast cancer surgery (7,15), with disabling effects on recovery outcomes and quality of life, hardly any studies have looked at preventive interventions from a psychological perspective. As psychological risk factors are vital, and the pathophysiology of both conditions largely unknown, interventions focusing on the psychological factors are largely needed.

Aims and objectives
The primary aim of the study is to develop and test an easily implementable strategy of preventing persistent pain and fatigue after breast cancer surgery. The intervention strategy involves a pre-operative hypnosis session and a post-operative, internet-based Acceptance and Commitment Therapy (iACT). The hypnosis was previously found effective in alleviating acute post-operative pain and fatigue in breast cancer patients, while ACT may be particularly well suited to cancer populations as it offers a model of healthy adaptation to difficult circumstances. Together they form an intervention strategy with both a preventive and a rehabilitative focus.
We have the following hypotheses: 1) Hypnosis is more effective than one-session mindfulness in relieving acute post-surgical pain and fatigue 2) Hypnosis alters markers of bodily stress responses and impacts immune reactivity associated with pain and fatigue.
3) Hypnosis + iACT results in less post-surgical pain and fatigue and fewer medical prescriptions for pain medication 3 months after surgery compared to one-session mindfulness + TAU 4) Hypnosis + iACT is favorable in a cost-utility analysis, and will result in fewer days of sick leave at 1 year follow-up compared to one-session mindfulness + TAU 5) Hypnosis + iACT results in less psychological distress and fewer medical prescriptions for psychotropic medications at the 3 and 6-month follow-ups compared to one-session mindfulness + TAU

Design
The study design involves a sequential, multiple assignment, randomized trial (SMART), where participants are randomly assigned to a treatment option at two stages, both pre-and post-surgery. By randomizing participants multiple times, we can assess the effectiveness of both interventions at each stage. We will thus be able to assess the short and long-term effectiveness of the pre-operative hypnosis, both alone and in combination with the postoperative iACT. Similarly, we will be able to assess the effectiveness of the post-operative iACT, both alone and in combination with the pre-operative hypnosis.

Outcome Measures
To assess hypothesis 1, subjective experiences of pain intensity, pain unpleasantness, and fatigue will be assessed using the Numerical Rating Scale (NRS) and Visual Analogue Scales (VAS) after surgery, upon discharge. Both intensity (i.e., amount) and unpleasantness of pain will be assessed to capture its sensory and affective dimensions. Two 100-mm visual analog scales (VASs) will be used to assess fatigue and muscle weakness, in line with previous breast cancer trials of post-surgical fatigue (26,41).
To assess hypothesis 2, we will measure cortisol in hair as a marker of hypothalamuspituitary-adrenal (HPA) axis activity, and two measures of inflammation -high sensitive CRP (hs-CRP) and lipopolysaccharide (LPS) reactivity. We consider hs-CRP an acceptable initial marker of systemic inflammation, whilst LPS will provide more nuanced and detailed results of immunological reactivity.
To assess hypothesis 3, NRS will be used to measure post-surgical pain, and FACIT-F (51) to measure post-surgical fatigue at 3 months follow-up. Registry data on pain-related prescriptions will further be extracted from The Norwegian Prescription Database (NorPD).
To assess hypothesis 4, we will use registry data to estimate the number of days participants in each group have been on sick leave (or other welfare benefits) during the year following surgery.
To assess hypothesis 5, we will measure psychological distress by the Hospital Anxiety and Depression Scale (52), as well as data on psychotropic prescriptions from The Norwegian Prescription Database (NorPD).

The Numeric Rating Scale (NRS):
The NRS is a discontinuous, self-report measure. It consists of a single item, in which the respondent is asked to rate the intensity of pain. This rate is done on an 11-point scale ranging from 0-10, anchored by verbal descriptors at either end of the scale. In the context of pain, the NRS has been proven to have good reliability and validity (Hawker, Mian, Kendzerska, & French, 2011; Johnson, 2005). It is a valid measure of pain intensity (0-10) that is less influenced by present mood state (54), and has been widely used to assess post-surgical pain in previous studies of women with breast cancer (3,7,8,55).

The Visual Analog Scale (VAS):
The VAS is a continuous, self-report measure comprised of either a horizontal or vertical line measured at exactly 100 mm. The line is anchored by verbal descriptors, and the respondent is asked to rate the intensity of their symptom by making a mark on the line. The distance between the end of the line, representing absence of the symptom, and the mark will be measured and a score ranging from 0 to 100 will be recorded. Similar to the NRS, the VAS can be used on a variety of symptoms and will here be used to assess fatigue and muscle

The Surgical Fear Questionnaire (SFQ):
The SFQ is a reliable and valid self-report instrument designed to assess fear of surgery, and it consists of 8 items which is scored on an 11-point scale ranging from 0 (not at all afraid) to 10 (very afraid). The items target different fears concerning surgery, namely fear of operation, anaesthesia, postoperative pain, side effects, health deterioration, failed operation, incomplete recovery and long duration of rehabilitation. The structure of the SFQ can best be described by a two-factor model, in which two subscales can be distinguished: fear of immediate consequences of surgery and fear of the long-term consequences (Theunissen et al., 2014).

Life Orientation Test -Revised (LOT-R)
The LOT-R is a 10 item self-report test meant to assess dispositional optimism. The respondents are asked to rate their agreement to various statements on a 5-point scale ranging from 0 (strongly disagree) to 4 (strongly agree). Three of the items assess optimism, three assess pessimism, and the remaining four are filler items that are not meant to be included in the scoring (Hinz et al., 2017).

Hospital Anxiety and Depression Scale (HADS)
The HADS is a scale specifically designed for patients with physical illness, and it makes no references to somatic symptoms such as fatigue, insomnia or headache. It is a selfadministered rating scale comprised of 14 items that are equally divided into two subscales:

The Pain Catastrophizing Scale (PCS)
The PCS is a self-report measure meant to assess catastrophizing. It is comprised of 13 items,

Insomnia Severity Index (ISI)
The ISI is a 7-item instrument, measuring severity, nature and impact of insomnia symptoms.
It is a brief screening and outcome measure for use in treatment research, and the scale corresponds in part to DSM-IV criteria for insomnia. The respondents are asked to rate their symptoms on a 5-pont scale ranging from 0 to 4, which assess the subject's current perception

Injustice Experience Questionnaire (IEQ)
The IEQ is a 12-item measure meant to assess the respondent's experience of injustice.
Injustice encompasses the degree of blame as well as the magnitude and irreparability of loss related to their health condition. The items therefore consists of thoughts and feelings related to injustice. Respondents are asked to rate their experience of injustice on a 5-point scale ranging from "not at all" to "all the time" (Sullivan et al., 2008). The scale was originally developed for patients with chronic pain conditions, but will in the current study be slightly adjusted to apply to patients diagnosed with breast cancer.

Eysenck Personality Questionnaire Revised for Neuroticism (EPQ-R Neuroticism)
The EPQR for Neuroticism is a measure meant to assess neuroticism, defined as a quantitative personality trait believed to predict an individual's vulnerability to neurotic disorders (Birley et al., 2006).There are several versions of the EPQR, each with satisfactory reliability and validity. Usually an EPQR involves other traits as well, but in this study only a 12-item EPQR for neuroticism will be used. Hence, the other traits will be excluded, and only neuroticism will be measured. As with most EPQRs the respondents will be asked to answer either "yes" or "no" on various statements regarding neuroticism and emotional stability (Francis & Pearson, 1988).

Blood analyses
The immune functional assay will consist in collecting whole blood samples using the

Data collection and management
Self-reported data and biomarker data will be collected pre-surgery (questionnaires, hair and blood), post-surgery upon discharge (brief phone survey), 3-4 weeks after surgery (blood), as well as 3 and 6 months after surgery (only questionnaire data). These time points either align with clinical follow-ups at the outpatient oncology department, or are responded to through an electronic link in the patients' homes to avoid unnecessary strain on the patient. Patient charts will be used to collect data on surgical procedures and potential complications during/after surgery. This will include information about the duration of the surgery, tumor-related variables, severity of acute post-surgical pain, and other relevant intra-operative variables.
Registry data on employment and benefit take-up and medical prescriptions will be obtained from FD-Trygd and the Norwegian Prescription Database (NorPD), respectively. To be able to assess for the effects of the interventions, data from NorPD and FD-Trygd will be obtained from inclusion in the trial until one year follow-up. The NorPD contains data about dispensed drugs in Norway, while FD-Trygd contains social security micro data for research. These data will be obtained retrospectively. The post-operative booklet that the patients receive as part of the iACT will also be collected at 6 months follow-up to assess if the patients used it as intended.
------------INSERT FIGURE 1-----------Survey data will be collected electronically by the use of laptops/smartphones. We will also utilize data from patients' medical records regarding surgical procedures and medical variables, as well as registry data, which will be linked to the survey data. Data from medical records as well as test results from blood samples will be entered directly into Viedoc by our study nurse. All data will be stored on a secure server at the hospital. The hospital already have a system in place for secure collection and storing of sensitive data which will be used.
A detailed plan for data management and sharing will be developed in collaboration with both Oslo University and the University of Oslo that shares the responsibility for data management in this study.

Implementation
The project will be administered from the Dept of Psychology, University of Oslo, which has the infrastructure to carry out such a study. Data will however be collected, stored and analyzed at Oslo University Hospital through Videoc which is an established and secure system for data collection, storing and management approved by the hospital. The trial will be run at the hospital in the Department of Breast and Endocrine surgery, which is a department with extensive experience in running clinical trials. Two study nurses will be employed to work in the out-patient department and on the ward with patient recruitment and biomarker assessments. A research assistant will be responsible for practical aspects of the trial as well as administering the follow-up data collection which we will attempt to align with the regular medical follow-ups following surgery to ensure a high response rate. Trained therapists and the PhD-student will be responsible for the pre-surgery hypnosis intervention. They will go through didactic and practical training, and complete supervised practice as part of their training. The hypnosis script is already translated and has been pilot tested in a small sample of breast cancer patients (Reme et al in progress). The iACT has been developed under the leadership of the co-PI of the study (Jacobsen), with input from our national and international partners (Linton & Flink), and user representatives. The user representatives will further be invited to participate in a focus group upon the completion of the post-operative intervention to discuss their experiences of the intervention and share any advice for modifications or changes to the interventions or procedures.
In order to disseminate the results to patients, clinicians, policy makers and the public, we are planning to co-host a seminar with the Norwegian Cancer Society for stakeholders and collaborators to present results from the trial. The Cancer Society will also communicate the research findings through their channels, which are well organized and far reaching.

Number and source of participants
The study will recruit and randomize 200 participants amongst patients from the Department of Breast and Endocrine surgery at Oslo University hospital (see sample size calculations for justification).

Recruitment
Eligible patients will be informed about the study by phone and on their first outpatient appointment at the clinic. A study nurse will be responsible for informing and recruiting patients to the trial.

Inclusion criteria
Patients must fulfill the following criteria to be eligible for inclusion in the study: • Women diagnosed with breast cancer and scheduled for surgery • Be able to provide informed consent

Randomization
The randomization procedure will be administered through the program Viedoc that uses an automated and valid randomization procedure. We intend to use a stratified randomization method in order to balance the influence of covariates. The main covariates of interest here is type of surgery (mastectomy vs breast-conserving surgery) and whether the newly diagnosed breast cancer is a relapse or not. Stratified randomization is achieved by generating a separate block for each combination of covariates, and subjects are assigned to the appropriate block of covariates. After all subjects have been identified and assigned into blocks, simple randomization is performed within each block to assign subjects to one of the groups.
Furthermore, a SMART randomization procedure will be applied, where the participants are randomized twice -pre-operative (hypnosis vs a one-session mindfulness), and post-operative (iACT vs treatment as usual).

Pre-operative hypnosis
The pre-operative intervention involves a brief hypnosis intervention that was previously found effective in reducing acute post-surgical pain and fatigue after breast cancer surgery (41). The hypnosis intervention will replicate a previous study of a 15-minute hypnosis intervention (41), and will be provided in a 15-minute session within 1 hour before surgery.
The scripted session includes a relaxation-based induction, suggestions for pleasant visual imagery, suggestions to experience relaxation and peace, and specific symptom-focused suggestions. The intervention will be further adapted and modified to the specific context of this study. Trained therapists will hold the session. Patients will be instructed to use hypnosis on their own following the intervention session. Based on data from the pilot trial, the Norwegian translation and administration of the hypnosis protocol lasts for 20 minutes.

Active control condition
Patients randomized to the control group will receive a mindfulness based app before surgery.
Mindfulness will be delivered via Headspace, a commercially available application which runs on all major smartphones, tablets and web browsers. The Headspace meditation scripts guide users through mindfulness meditations using both audio and visual materials. Internet based mindfulness meditation programs such as Headspace have shown significant effects on chronic pain and fatigue in breast cancer patients (56). However, the referred studies all entail numerous sessions of mindfulness with some degree of therapist involvement. We therefore believe a single session of mindfulness delivered through an app, constitute an active and ethically sound control condition.

Post-surgical intervention
After surgery, participants will be randomized again to either a post-surgical intervention or to treatment as usual. The post-surgical intervention is comprised of a web-based ACT intervention with the cognitive activation model of stress as theoretical vantage points. The intervention consists of videos in combination with a work booklet targeting three main processes derived from the ACT hexaflex model (57), and delivered in two stages. In the initial stage, the intervention has several videos that is built to involve the patient in a

Comparison of interventions
Pre-surgery intervention versus active control: Hypnosis and mindfulness are commonly regarded as supplements or integrative parts of an ACT intervention (43). They both start by focusing the patient's attention in similar ways, but proceed to utilize that focused state into different means. The pre-operative hypnosis here is used with a specific purpose and intent of lessening pain and promote coping. The pre-operative one-session mindfulness has a specific purpose and intent to focus on one thing like the breath, sounds or the body. Thus, both techniques guide the patients experience and use suggestion, but the end goals are fundamentally different.

Drop out and non-compliance
Participants who no longer wish to participate in the study can inform the research group of their decision by notifying the study nurse, the trial coordinator or the PI. The trial coordinator will in any case contact participants who drop out by phone, and ask if they are willing to report the reason for withdrawal. If reasons are provided, these will be registered on a dedicated drop out form. Whether they only want to withdraw from the interventions, or if they also want to withdraw from future follow-ups, will also be registered. Finally, it will be registered if the participant gives permission for use of data that has already been collected, or if they want these to be deleted. Participants who drop out of the study will still be included in the intention-to-treat (ITT) analyses, unless they required all their data deleted.

Sample size and power
Sample size is estimated for both of the primary outcomes. Previous trials with similar interventions have demonstrated moderate/large effect sizes on pain and fatigue (26,60).
However, compared to these studies, we expect more heterogeneity in our data as our study population will undergo several medical treatments during the trial (e.g. radiotherapy or chemotherapy after surgery). We thus expect a minimum difference of one point on NRS (0-10) and 3 points on FACIT-F (which corresponds to patients reporting being "slightly better"). Based on previous studies, it is expected that the control group scores 5 (SD: 2.4) on NRS at 3 months follow-up (25), and 18 on FACIT-F (26). With power set at 0.80 and twotailed a set at .05, the number needed in each group to detect the change in pain is n=92, and in fatigue n=87. To account for attrition and loss to follow-up, we plan to include 100 patients in each group.

Statistical analyses
Effect analyses of primary and secondary outcomes will be performed according to both the intention-to-treat principle and per protocol. The effect analysis of the primary outcomes will involve a comparison of pain and fatigue levels at 3 months follow-up. Additionally, they will be analyzed using linear mixed models (also referred to as multilevel models) at the 3 different time points (post-surgery, 3-and 6-months f/u). Multilevel modelling is a flexible statistical approach that can handle non-balanced data with missing entries and repeated observations (61). The health economic analyses will investigate differences in treatment costs, as well as indirect costs related to work (dis)ability and sick-leave. A cost-utility analysis will be performed estimating costs per quality-adjusted life year.

Health Economic analysis
The health economic analyses will investigate differences in treatment costs, as well as indirect costs related to work (dis)ability and sick-leave. The cost-utility analysis will be performed according to well-established methods, taking into account the direct (pre-and post-operative interventions) costs and quality of life (generated from EQ-5D).
performed estimating costs per quality-adjusted life year (QALY).

Compliance
Regular supervision will be conducted with the therapists conducting the pre-operative hypnosis in order to secure compliance to the protocol. The PI and co-PI of the study will be in charge of the supervision. They are both experienced psychologists with a clinical specialization and they are certified in this particular hypnosis intervention. In order to assess compliance with the post-operative intervention, we will have user statistics logged on the web-page i.e. what videos have been used, by which ID and when. This will be used in combination with collecting the work-booklets to see whether the patient has performed different tasks related to the videos. If accepted by GDPR standards, we will associate the booklet with the given video using an unidentified study ID yielding a rate of completion for the post-operative intervention.

Confidentiality
Participant reported outcome measures (PROMs) will be completed electronically using the ViedocMe functionality available in Viedoc. Study staff will create a ViedocMe account for each participant in the participant's Clinic View in Viedoc and provide an unique log-in profile (user name, pin-code, and ViedocMe web-address) for each participant. Participants are to use this information to log in to their personal ViedocMe account. The questionnaires in ViedocMe will only be available for completion for three days prior to their clinical visitations.

Discussion
Breast cancer is the most common form of cancer among women (1), and a majority of women report persistent psychological and physiological symptoms after breast-cancer surgery (3)(4)(5). Chronic post-surgical pain and fatigue are the most common sequelas (6,11) . This is a both a major clinical problem, with prevalence rates ranging up to 60% (6) , and a socioeconomic burden on the health care system (62). Studies on preventive interventions are scarce, and those that have been carried out have not been sufficiently replicated.
This study will to our knowledge be the first study to investigate the combined effects of a pre-operative hypnosis intervention and a web-based post-operative ACT intervention in women about to undergo breast cancer surgery. It will also be among the very few attempts worldwide to prevent the incidence of pain and fatigue after breast cancer surgery applying a psychological approach. This study design has several strengths. The outcome measures are valid and reliable, involving both self-report measures, objective registry data, and biomarker data, and the study will contribute to the need of rigorous clinical trials within this field of research. The project results will be highly relevant to all health care personnel involved in breast cancer care, but also to the larger community of clinicians and researchers within the field of chronic pain and fatigue.

Trial Status
The trial will start recruiting in April 2020.